New hope for people with sickle cell anemia

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In tropical regions of the world where the parasite-borne disease malaria is prevalent, people with a single copy of a particular genetic mutation have a survival advantage. Over time, people from these regions have migrated, had children, and in some cases married each other. Some of their children inherit two copies of the mutation.

While inheriting one copy of the mutation confers a benefit, inheriting two copies is a tragedy. Children born with two copies of the genetic mutation have sickle cell anemia, a painful disease that affects the red blood cells and is curable only in rare instances.

A recent clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) found that the drug Hydrea (hydroxyurea) significantly reduced painful episodes in adults with a severe form of sickle cell anemia. NHLBI is a component of the National Institutes of Health (NIH).

Hydrea is approved by the Food and Drug Administration to treat certain types of cancer. On the basis of the new clinical trial findings, FDA is encouraging Hydrea's manufacturer, Bristol-Myers Squibb, to apply for approval of the drug to treat sickle cell anemia.

"FDA will consider it a priority application so that sickle cell anemia can be added to the indications for Hydrea, if the data show that [the drug] is indeed safe and effective," said Anthony Murgo, M.D., a medical officer in the division of oncology at FDA's Center for Drug Evaluation and Research.

Genetic Defect Changes Cell Shape
The genetic defect that causes sickle cell anemia affects hemoglobin, a component of red blood cells. Hemoglobin's job is to carry oxygen to all the cells and tissues of the body. Red blood cells that contain normal hemoglobin are soft and round. Their soft texture enables them to squeeze through the body's small blood vessels.

People with sickle cell anemia, however, have a type of abnormal hemoglobin called hemoglobin S. (Normal hemoglobin is called hemoglobin A.) A genetic error makes the hemoglobin molecules stick together in long, rigid rods after they release oxygen. These rods cause the red blood cells to become hard and sickle-shaped, unable to squeeze through tiny blood vessels. The misshapen cells can get stuck in the small blood vessels, causing a blockage that deprives the body's cells and tissues of blood and oxygen.

When this happens "it's like having mini heart attacks throughout the entire body," said Duane R. Bonds, M.D., leader of the sickle cell disease scientific research group at NHLBI in Bethesda, Md.

"A heart attack is painful because the blood flow to the heart is interrupted. In sickle cell anemia, the blood flow can be interrupted to any of the major organs, causing severe pain and organ damage at the site of the blood flow blockage."

These painful "crises," as they are called, damage the lungs, kidneys, liver, bones, and other organs and tissues. Recurrence of these episodes is the most disabling feature of sickle cell anemia. They can cause leg ulcers, blindness, and many other health problems, depending upon where in the body the blood flow blockage occurs. A blockage in the brain can cause a stroke, which may result in paralysis or death.

The body, recognizing that the sickled cells are abnormal; destroys them at a faster rate than it can replace them. This causes a type of anemia, a shortage of red blood cells. Symptoms of anemia include extreme fatigue and susceptibility to infection.

Penicillin Treatment
An important breakthrough occurred in 1986 when an NHLBI-sponsored study found that young children with sickle cell anemia who took penicillin twice a day by mouth had much lower rates of S. pneumoniae infection than a similar group of children who received a placebo.

In 1987, an expert panel convened by NHLBI recommended that all infants born in the United States be screened for sickle cell anemia so that children with the disease could be identified early and offered treatment with penicillin. Forty-two states now have newborn screening programs, according to Bonds. NHLBI also recommends that affected infants get daily penicillin therapy beginning by the age of 3 months.

In the first year of life, children with sickle cell anemia are protected from blood flow blockages by the presence of fetal hemoglobin.

"Fetal hemoglobin is the hemoglobin that all of us produce before we're born," explained Bonds. Fetal hemoglobin physically blocks hemoglobin S, preventing it from forming the long, rigid rods that lead to sickling of the red blood cells. Several weeks before birth, however, the fetus' bone marrow usually begins to shut down the production of fetal hemoglobin and starts making adult hemoglobin instead. At birth, an infant's red blood cells contain roughly equal amounts of fetal and adult hemoglobin.

By the time the child is 6 months old, it has usually stopped making any fetal hemoglobin. As the level of fetal hemoglobin in the child's blood falls, explained Bonds, there is no longer anything to prevent the red blood cells from becoming sickle-shaped and getting stuck in the blood vessels, causing a painful crisis.

The symptoms of a painful crisis may be relieved by giving patients fluids and painkillers, said Lilia Talarico, M.D., a medical officer in the division of gastrointestinal and hematologic drug products in FDA's Center for Drug Evaluation and Research. However, no FDA-approved treatment is currently available to prevent painful crises from occurring.

Life Expectancy Improves
Despite the absence of an effective treatment, life expectancy for individuals with sickle cell anemia has improved, said Bonds, as a result of early identification through neonatal screening, early initiation of penicillin therapy, close medical monitoring, and early intervention to relieve the symptoms of a painful episode. A recent study found that half of all patients with sickle cell anemia survive into their 40s.

Rates of early death are highest among those with a severe form of the disease. "Between 10 and 15 percent of parents will have three or more painful crises per year," said Bonds. "The more crises you have per year, the greater your chances of dying prematurely. Your organs become more damaged when they are chronically not receiving enough blood and oxygen."

Some people continue to produce fetal hemoglobin throughout their lives. A study of the life expectancy of people with sickle cell anemia found that adults with high levels of fetal hemoglobin lived longer than those who had low levels.

People with sickle cell anemia who suffer strokes or infections, who are pregnant, or who must undergo surgery may be treated with blood transfusions. Risks of this treatment include the possibility of acquiring a viral illness such as hepatitis and the possibility of organ damage caused by iron overload.

Sickle cell anemia can be cured by a bone marrow transplant, which replaces the defective red blood cells with healthy cells from a donor. But a transplant is not a realistic option for most people with sickle cell anemia, according to Bonds, because of a shortage of compatible donors and because of the risks presented by the drug regimen that is required to prepare a patient for a transplant.

"First you give drugs to kill off the patient's marrow, then you do the transplant to replace the marrow." But the powerful drugs given to kill the patient's bone marrow can be dangerous for someone who has had a stroke or is at risk for stroke, she said.

In January 1995, NHLBI announced the successful conclusion of a five-year, multicenter trial of Hydrea in the treatment of sickle cell anemia. The study involved 299 patients ages 18 and older who were recruited at 21 medical centers in the United States.

All patients had experienced at least three painful crises in the year before ',hey entered the trial. Half of the patients received Hydrea and half received a placebo. Neither the patients nor their doctors knew who was taking the drug and who was taking the placebo. Patients who took Hydrea had roughly half as many painful crises as those who took the inactive pill.

The trial had been scheduled to conclude in May 1995. However, scientists involved found the results so compelling that they stopped the study early and no-rifled doctors of the results so that all patients who might benefit could be offered the treatment. A report of the trial's findings was published in the May 1995 New England Journal of Medicine.

Hydrea Studies
Hydrea is approved by FDA to treat certain types of leukemia and other cancers. Doctors have been interested in Hydrea for the treatment of sickle cell anemia for about 10 years, since pilot studies in humans showed that the drag could increase the level of fetal hemoglobin in red blood cells.

Because Hydrea is already on the market for other uses, it was unnecessary for FDA to issue a Treatment IND (investigational new drug) to make the drug available to patients with sickle cell anemia, said FDA's Murgo. A Treatment IND is a mechanism used by FDA to make investigational new drugs available to patients while they are under study.

As with other approved medications, doctors may prescribe Hydrea for sickle cell anemia if in their professional judgment a patient will benefit from the treatment.

"We are excited about the report [of the Hydrea clinical trial]," said Murgo. "But until the manufacturer [of the drug] submits the detailed data for us to review, [the agency] cannot approve the drug to treat sickle cell anemia."

Bonds, who was the project officer for the multicenter study, cautioned that Hydrea treatment is not appropriate for every patient.

"We only recommend it for patients over 18 who have had at least three painful crises in the previous year. The patients have to be monitored very carefully. They must have a blood test every two weeks to ensure that their blood count is not depressed to a level where they might be at risk for infection or bleeding."

Hydrea should not be prescribed for patients who are likely to become pregnant or who are unable to follow instructions regarding treatment, said Murgo.

Many questions about Hydrea in the treatment of sickle cell anemia remain unanswered, said Bonds. Doctors do not know what the most effective and least toxic dose of the drag is or whether taking it for many years presents health risks.

Some doctors prescribe Hydrea to treat polycythemia vere, a disease in which the number of red blood cells increases abnormally. Some evidence suggests that the drug may cause leukemia in a few of these patients, both Murgo and Bonds said.

However, they added, patients with polycythemia vera already have a higher-than-average risk of getting leukemia, so it is unclear whether the leukemia is caused by Hydrea or whether the patients would have developed it anyway.

NHLBI is planning a five-year follow-up study of patients who took part in the Hydrea trial to see whether any of them develop leukemia or other problems that may result from long-term use of the drug. Another study, which began in January 1995, is looking at the safety and effectiveness of Hydrea in children ages 5 to 15 who have sickle cell anemia.

Research continues on other possible ways of reducing the occurrence of painful sickle cell episodes, by increasing the production of fetal hemoglobin. For example, NIH scientists are studying whether a combined regimen of Hydrea and erythropoietin, a hormone that increases the production of red blood cells, is less toxic and more effective than Hydrea alone. (Erythropoietin is licensed by FDA to treat anemia in certain patients.) Studies are also under way to determine the safety and efficacy of butyrate, an experimental drag that can stimulate production of fetal hemoglobin.

NHLBI recently funded three centers that will try to develop gene therapy for sickle cell anemia, said Bonds. "If you could replace the abnormal genes, you could cure the disease. However, there are significant technical problems involved in making gene therapy work."

Because of these problems, gene therapy is unlikely to be a reality for many years, she said. Nevertheless, she said she is optimistic that new, effective treatments for sickle cell anemia will be developed in the future.

"I like to tell people that [the results of the Hydrea study] will one day be likened to [the discovery of] insulin or penicillin. Those drags were the first major breakthroughs for the treatment of diabetes and severe bacterial infections, although other agents have since [been introduced] to treat those diseases."

SICKLE CELL INHERITANCE
In the United States, sickle cell anemia is most common among African Americans. Every year, about 1 in 400 African-American infants is born with the disease after inheriting the genetic mutation them both parents.

People who have only one copy of the mutation are said to have sickle cell trait. It is estimated that 1 in 12 African Americans has sickle cell trait. People with sickle cell trait are usually healthy, although they can pass the mutation on to their children.

A child conceived by two people with sickle cell trait has one chance in two of also having sickle cell trait, one chance in four of having sickle cell anemia, and one chance in four of inheriting neither the trait nor the disease, according to Lilia Talarico, M.D., a medical officer in the division of gastrointestinal and hematologic drug products in FDA's Center for Drug Evaluation and Research.

The disease can also occur among non-African Americans. "People whose ancestors came from parts of the world where malaria was prevalent are potentially carders of the sickle gene," said Duane R. Bonds, M.D., of the National Heart, Lung, and Blood Institute. "In addition to people of African descent, people whose ancestors came from the Mediterranean basin--Greece, Italy, Sardinia--may also carry the gene. The sickle gene is also found in parts of India and the Arabian peninsula."

In the past, individuals with sickle cell anemia often died in childhood. A 1973 study estimated that half of those with the disease died by the age of 14. A frequent cause of death was bacterial infection by the organism Streptococcus pneumoniae. Children with sickle cell anemia are highly susceptible to infections because they lose the function of their spleen, which provides protection against bacterial infections.